Regulation of mouse renal CYP2J5 expression by sex hormones
Regulation of mouse renal CYP2J5 expression by sex hormones
复制标题
DOI：
10.1124/mol.65.3.730
复制
发表时间：
2004-03-01
影响因子：
3.6
通讯作者：
Zeldin, DC
中科院分区：
文献类型：
--
作者：
Ma, J;Graves, J;Zeldin, DC
小鼠CYP 2 J5在肾脏中含量丰富，并在花生四烯酸代谢为环氧二十碳三烯酸中具有活性。从小鼠肾脏制备的微粒体的蛋白质印迹证明，青春期后，雄性小鼠中的CYP 2 J5蛋白水平高于雌性小鼠。北方分析显示，CYP 2 J5转录本在成年男性肾脏中比女性肾脏中更丰富，表明肾脏CYP 2 J5表达的性别差异在翻译前水平上受到调节。雄性小鼠的去势导致肾脏CYP 2 J5表达降低，并且用5 α-二氢睾酮处理去势雄性小鼠或雌性小鼠使表达增加至接近完整雄性小鼠中的表达水平。相比之下，用17 β-雌二醇治疗卵巢切除的雌性小鼠或去势的雄性小鼠导致CYP 2 J5表达进一步降低。生长激素缺乏（lit/lit）小鼠对去势和5 α-二氢睾酮治疗的反应相似，表明雄激素效应不是由生长激素分泌模式的改变介导的。缺乏功能性雄激素受体（Tfm半合子）的小鼠肾脏CYP 2 J5水平降低，对5 α-二氢睾酮治疗无反应。类似地，用雄激素拮抗剂氟替卡松处理的野生型雄性小鼠表现出肾脏CYP 2 J5水平降低。已知雌性雌激素受体α敲除（alphaERKO）小鼠循环睾酮水平升高，与野生型雌性小鼠相比，肾脏CYP 2 J5表达显着增加，这些差异可通过卵巢切除术或氟他胺治疗消除。基于这些数据，我们得出结论，CYP 2 J5的肾脏表达上调雄激素和下调雌激素。
Mouse CYP2J5 is abundant in kidney and active in the metabolism of arachidonic acid to epoxyeicosatrienoic acids. Western blots of microsomes prepared from mouse kidneys demonstrate that after puberty, CYP2J5 protein is present at higher levels in male mice than in female mice. Northern analysis reveals that CYP2J5 transcripts are more abundant in adult male versus female kidneys, indicating that gender differences in renal CYP2J5 expression are regulated at a pretranslational level. Castration of male mice results in decreased renal CYP2J5 expression, and treatment of castrated male mice or female mice with 5alpha-dihydrotestosterone increases expression to levels that approximate those in intact male mice. In contrast, treatment of ovariectomized female mice or castrated male mice with 17beta-estradiol causes a further reduction in CYP2J5 expression. Growth hormone-deficient (lit/lit) mice respond similarly to castration and 5alpha-dihydrotestosterone treatment, indicating that the androgen effects are not mediated by alterations in the growth hormone secretory pattern. Mice that lack a functional androgen receptor (Tfm hemizygous) have reduced levels of renal CYP2J5 and do not respond to 5alpha-dihydrotestosterone treatment. Similarly, wild-type male mice treated with flutamide, an androgen antagonist, exhibit reduced renal CYP2J5 levels. Female estrogen receptor-alpha knockout (alphaERKO) mice, which are known to have elevated circulating testosterone levels, have significantly increased renal CYP2J5 expression compared with wild-type female mice, and these differences are abrogated by ovariectomy or treatment with flutamide. Based on these data, we conclude that the renal expression of CYP2J5 is up-regulated by androgen and downregulated by estrogen.